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Induction of c-fos and c-jun gene expression and apoptosis by reactive oxygen species (ROS) and reactive nitrogen species (RNS) in lung epithelial cells was demonstrated. RLE-6TN cells, a rat lung type II epithelial cell line, were exposed to 0 to 1 millimolar (mM) hydrogen-peroxide (7722841), nitric-oxide (10102439), or peroxynitrite (26404660) for 2 hours. Peroxynitrite was produced exogenously by reacting hydrogen-peroxide with sodium-nitrite or generated in-situ from 3-morpholinosydnonimine. Nitric-oxide was generated in-situ from spermine-1,3-propanediamine-N-(4-(1-(3- aminopropyl)-2- hydroxy-2-nitrosohydrazino)-butyl) or from S-nitro-N- acetylpenicillamine. The RNA was extracted from some cells and the level of expression of c-fos and c-jun mRNA was determined by Northern blotting. The concentrations of c-fos and c-jun proteins was determined by Western blotting. The extent of binding of activator-protein-1-transcription-factor (AP-1-TF) to AP-1 consensus DNA sequences was measured by an electrophoresis mobility shift assay. Induction of apoptosis was evaluated by a flow cytometric assay based on identifying cells with hypodiploid DNA and by a DNA laddering assay. Nitric-oxide and hydrogen-peroxide significantly increased the level of c-fos and c-jun mRNA expression, c-fos and c- jun protein concentrations, level of AP-1-TF binding to AP-1 consensus DNA sequences, and cellular apoptosis. Peroxynitrite applied exogenously to the cells or that was generated in-situ had no significant effect on these parameters. The authors conclude that nitric-oxide or hydrogen-peroxide increases early response gene expression leading to apoptosis in lung epithelial cells. Peroxynitrite did not cause these effects. Induction of c-fos and c- jun transcripts by ROS and RNS may play a critical role in the development of pulmonary diseases which are associated with reactive metabolites.